Growth factor and growth factor receptor genes, known as proto-oncogenes, play important roles in the pathology of human tumors such as breast cancer (Aronson et al., Science, Vol. 254, pp. 1146-1153, 1991). Having homology to epidermal growth factor (EGF) receptor, the HER2 (Human EGF receptor-2) gene encodes transmembrane-type glycoprotein, and this receptor possesses tyrosine kinase activity (Akiyama et al., Science, Vol. 232, pp. 1644-1646, 1986). HER2 is found in human breast cancer and ovarian cancer (Slamon et al., Science, Vol. 244, pp. 707-712, 1989) and is also found in prostate cancer (Lyne et al., Proceedings of the American Association for Cancer Research, Vol. 37, p. 243, 1996) and gastric cancer (Yonemura et al., Cancer Research, Vol. 51, p. 1034, 1991). In addition, the substrate for HER2 tyrosine kinase is found in 90% of cases of pancreatic cancer. Transgenic mice incorporating the HER2 gene develop breast cancer as they grow (Guy et al., Proceedings of the National Academy of Science, USA, Vol. 89, pp. 10578-10582, 1992).
An antibody against HER2 was shown to suppress in vitro proliferation of cancer cells (McKenzie et al., Oncogene, Vol. 4, pp. 543-548, 1989); in addition, a human monoclonal antibody against HER2 provided encouraging results in a clinical study in breast cancer patients (Baselga et al., Journal of Clinical Oncology, Vol. 14, pp. 737-744, 1996).
These antibodies interfere with growth factors to bind to HER2 and inhibit the activation of tyrosine kinase. Because these antibodies were thus shown to suppress the progression of cancer in breast cancer patients, drugs which directly inhibit HER2 tyrosine kinase were shown to be potentially effective as therapeutic drugs for breast cancer (Hayes, Journal of Clinical Oncology, Vol. 14, pp. 697-699, 1996).
As a compound that inhibits receptor type tyrosine kinases, including HER2, Japanese Patent Unexamined Publication No. 60571/1999 discloses a compound represented by the formula: wherein R1 is an aromatic heterocyclic group which may be substituted; X1 is an oxygen atom, an optionally oxidized sulfur atom, —C(═O)— or —CH(OH)—; Y1, is CH or N; m1 is an integer from 0 to 10; n1 is an integer from 1 to 5; the cyclic group: is an aromatic azole group which may be substituted; Ring A1 may be further substituted.
The conventional compounds that inhibit tyrosine kinase are not satisfied as drugs because they have some problems in efficacy, toxicity and the like. And, there is demand for the development of a compound which possesses excellent tyrosine kinase-inhibiting activity, which is of low toxicity, and which is satisfactory as a pharmaceutical.